DESCRIPTION (applicant's abstract): Recent demonstrations of the presence of antibodies in peripheral fluids to degradation products of central neurotransmitter receptors has led to studies to identify the potential clinical relevance of these findings. Elevated levels of autoantibodies to neurotransmitter receptors have been found in the serum of individuals suffering from epilepsy and ischemic stroke. The effects of drug abuse on the immune system has been widely studied, with these studies generally focused on classic immune parameters. Preliminary data have shown elevated levels of autoantibodies to antigenic fragments of the mu-delta receptor complex in the plasma of human opiate abusers and in heroin self-administering rats. Recent evidence indicate that immunocompetent microglia in the brain are capable of developing an antigen stimulated humoral immunity. This application proposes experiments to establish assays for autoantibodies for polypeptide degradation products of the mu and delta opioid receptor subunits and to assess the presence of these autoantibodies in mu receptor (expressing transfected CHO and C6 glioma cells) and delta receptor (NG 108 15 neuroblastoma x glioma) expressing cell lines and then in sera, CSF and brain regions of rats intravenously self-administering cocaine, heroin and cocaine/heroin combinations. It is hypothesized that abuse of agonists for opiate receptors may result in the breakdown of these receptors producing antigenic peptide fragments that can serve as exogenic substances which are recognized by the immune system resulting in the production of autoantibodies to the mu and delta opioid receptor subunits. The potential for the involvement of autoantibodies to neurotransmitter receptors in the chronic abuse of drugs is significant and could identify new mechanisms for determining vulnerability, clinical progress, the propensity for relapse and effects that are often difficult to understand with current concepts of brain plasticity (directed toxicities).